Objective: Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle. Conclusions: Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.
Background: Pulmonary hypertension in the context of heart failure with preserved ejection fraction (PH-HFpEF) is the most common cause of PH worldwide. However, major pathways involved in the regulation of PH-HFpEF are still not well understood. We have previously reported a role of skeletal muscle sirtuin-3 (SIRT3) in PH-HFpEF. In the present study, we aimed to investigate how skeletal muscle SIRT3 defects remotely affect pulmonary vascular health in PH-HFpEF. Methods and Results: Using global mass spectrometry-based comparative analysis, we found increased secretion of lysyl oxidase homolog 2 (LOXL2) in SIRT3-deficeint skeletal muscle. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3 skm-/- mice, rats with experimental PH-HFpEF (SU5416/Obese ZSF1, Ob-Su), and patients with PH-HFpEF. Additionally, expression levels of canopy fibroblast growth factor signaling regulator 2 (CNPY2), a known angiogenic and proliferative factor, were increased in PASMCs obtained from Sirt3 skm-/- mice and Ob-Su rats, suggesting a potential role of CNPY2 as a molecular target of skeletal muscle SIRT3-LOXL2 signaling in PASMCs. Treatment with LOXL2 recombinant protein resulted in increased levels of CNPY2, PCNA, and cellular proliferation in vitro in PASMCs. LOXL2 treatment, as well as CNPY2 overexpression, decreased the levels of tumor suppressor p53 in PASMCs. In addition, CNPY2 overexpression also decreased CNPY2 expression level in PASMCs. Media conditioned by SIRT3-deficient skeletal muscle cells increased CNPY2 expression in PASMCs, concomitant with decreased p53 and enhanced PCNA. Finally, knockdown of both SIRT3 and LOXL2 in skeletal muscle cells and/or suppression of LOXL2 with β-aminopropionitrile (BAPN) restored CNPY2, p53, and PCNA levels in PASMCs. Conclusions: These studies reveal a new endocrine signaling axis that links skeletal muscle SIRT3 deficiency to remote CNPY2 -p53 regulation in the pulmonary vasculature through myokine LOXL2. Our data may also identify skeletal muscle SIRT3, myokine LOXL2, CNPY2, and p53 as potential targets for the treatment of PH-HFpEF.
Introduction: Pulmonary hypertension due to left heart disease (PH-LHD; Group 2), particularly in the context of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide. At present, no specific effective therapy has been identified mainly due to the fact that major pathways involved in the regulation of PH-HFpEF are still not well understood. Results: We have recently reported on a role of skeletal muscle sirtuin-3 (SIRT3) in modulating PH-HFpEF. Using skeletal muscle-specific SIRT3 knockout mice ( Sirt3 skm-/- ), we showed that absence of SIRT3 in skeletal muscle drastically reduced the pulmonary vascular tree accompanied by vascular proliferative remodeling. Interestingly, we found that expression levels of the tumor suppressor WW domain-containing oxidoreductase (WWOX) were decreased in pulmonary arterial smooth muscle cells (PASMCs) obtained from Sirt3 skm-/- mice, while no changes in SIRT3 activation levels were detected. Reduced WWOX expression levels were also found in PASMCs isolated from SU5416/Obese ZSF1 (Ob-Su) rat model of PH-HFpEF, in which the levels of SIRT3 activation were found to be decreased in skeletal muscle, but not in the lungs and PASMCs. No changes of WWOX levels were observed in skeletal muscle of Ob-Su rats or in pulmonary artery endothelial cells (PAECs) treated with plasma obtained from Ob-Su rats. Conclusions: Since reduction of WWOX in PASMCs has been shown to promote cell proliferation, HIF1α stabilization and pulmonary arterial hypertension (PAH; Group 1), our data suggest a potential role of WWOX in mediating skeletal muscle SIRT3 deficiency-associated remote pulmonary vascular remodeling in PH-HFpEF.
Background: Pulmonary hypertension in heart failure with preserved ejection fraction (PH-HFpEF) is the most common cause of PH worldwide. It is closely linked to risk factors for metabolic syndrome, including obesity and diabetes - factors known to increase proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), leading to pulmonary vascular remodeling. Qualitative studies have shown that patients with progressive vascular abnormalities develop more severe symptoms and suffer frequent hospitalization. However, underlying mechanisms involved in the regulation of pulmonary vascular remodeling in metabolic syndrome-associated PH-HFpEF are still unclear. Aim: We have recently observed decreased levels of the tumor suppressor WW domain-containing oxidoreductase (WWOX), which plays a housekeeping role in repressing cellular proliferation, in PASMCs isolated from rats with experimental PH-HFpEF and human subjects with obesity and diabetes. As microRNAs (miRNAs) have been shown to regulate WWOX expression in cancers, here we aimed at examining the involvement of miRNAs in WWOX-associated pulmonary vasculature regulation in metabolic syndrome-associated PH-HFpEF. Methods and Results: Among miRNAs that have been associated with reduced WWOX expression, including miR -134-5p, -153-3p, -29a-3b, -29b-3p and -187-5p, we found that miR-134-5p was significantly increased in PASMCs of obese and diabetic subjects. To determine the role of miR-134-5p in the regulation of WWOX in the pulmonary vasculature, we applied exogenous miR-134-5p to human PASMCs. Treatment with miR-134-5p decreased WWOX expression, increased PCNA expression (a cell proliferation marker) and enhanced cellular proliferation. Additionally, human PASMCs challenged with high concentration of glucose, palmitic acid and insulin, which mimic hyperglycemic, hyperlipidemic and hyperinsulinemic conditions, exhibited increased miR-134-5p, accompanied by elevated cellular proliferation. Conclusions: These studies suggest that miR-134-5p may have a potential role in metabolic syndrome-associated PH-HFpEF through regulating WWOX in the pulmonary vasculature. These studies identify miR-134-5p as a potential therapeutic target for the treatment of metabolic syndrome-associated PH-HFpEF. This project was funded, in part, with support from the NIH NHLBI Short-Term Training Program in Biomedical Sciences Grant funded, in part by T35HL110854 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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